Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report.

Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment.

Modified Plasma Cytokine Profile in Occupational Dermatitis.

BACKGROUND: Despite significant progress in the diagnosis of contact dermatitis, the identification by specific tests or biomarkers remains an unsolved issue, particularly when needed for the confirmation of the occupational origin of the disease. OBJECTIVE: To characterize the plasma proteome profile in occupational dermatitis in workers of paint industry. METHODS: The study has a case-control design, comparing exposed workers with and without occupational contact dermatitis, matched for age, gender, occupational history, and comorbidities. An immunological assay (Human XL Cytokine Array Kit - ARY022B, R&D Systems) was used to measure the plasma levels of 105 cytokines and chemokines in a pooled sample of the cases and a pooled sample of the controls. RESULTS: A 1.5-fold increase was noticed for interleukin 3, interleukin 10, and leptin in cases, as compared to controls. Fibroblast growth factor-7 and growth/differentiation factor-15 showed a 1.4-fold increase, while interleukin 19, interleukin 31, and macrophage inflammatory protein 3a.had only a 1.3- fold increase. The leukemia inhibitory factor was the only plasma cytokine that showed a 1.3-fold decrease. All other cytokines had a variation of less than 1.2-fold between cases and controls. CONCLUSION: The recognition of the molecular signatures is very important for an accurate and indisputable diagnosis of occupational contact dermatitis. In workers from the paint industry, plasma levels of interleukins 3, 10, 13 and 19, fibroblast growth factor-7, and growth/differentiation factor-15, together with leukemia inducible factor, may differentiate subjects with contact dermatitis from those without skin lesions.

Gastrointestinal cancer stem cells as targets for innovative immunotherapy.

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.

Recent advances in gastric cancer early diagnosis.

Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.

MECHANISMS OF THROMBOSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Thrombotic events are highly prevalent in systemic lupus erythematosus (SLE). Antiphospholipid antibodies play an essential role in promoting thrombosis by activating several intracellular signaling pathways (TLR4, p38MAPK, NFkB) in platelets, monocytes and endothelial cells. New therapeutic opportunities might be offered by addressing these molecular targets. Chronic inflammatory status, the degree of disease activity and accelerated atherosclerosis are also responsible for the thrombotic phenotype in patients with SLE. The aim of this review is to highlight thrombosis mechanisms and to look for possible connection between SLE, antiphospholipid antibodies and cancer, especially myeloproliferative neoplasms.

Plasticity of regulatory T cells under cytokine pressure.

CD4+ T helper (Th) cells have been divided into different subsets as defined by their cytokine products and functions after their activation. CD4+ T cell subsets are continuously discovered and until now Th1, Th2, Th9, Th17, and regulatory T (Treg) cells have been almost unanimously recognized but yet not completely characterized. The selective production of cytokines by each of the subsets is probably the master key of the mechanisms of immune regulation. The cytokine milieu is extremely important on deciding the fate of T cells. Generally, more than one cytokine is needed for differentiating to a particular lineage and just recently it was shown that this status quo of commitment could be challenged. It is well known that cytokines bind to Type I/II cytokine receptors signaling via Janus kinases (JAKs) followed by activation of Signal Transducer and Activator of Transcription (STAT). STAT molecules work together with other transcription factors (Foxp3, RORgammat and RORalpha, T-bet, GATA3, Runx 1, NFAT, etc.) also controlled by cytokines, in modulating the Th phenotype and functions. In this review, we analyze the plasticity of Treg population focusing on the most recent discoveries on how microenvironmental cytokines refine/modify Treg phenotype and function, thus changing their fate.